An Open-Label, Phase I Study of Systemic Hedgehog Pathway Antagonist, GDC-0449, in Patients With Locally Advanced or Metastatic Solid Tumors That Are Refractory to Standard Therapy or For Whom No Standard Therapy Exists

To evaluate the safety and tolerability of escalating doses of systemic Hedgehog antagonist GDC-0449 in patients with locally advanced or metastatic solid tumors.

To estimate the maximum tolerated dose of GDC-0449 in these patients.

To define the dose-limiting toxicities of GDC-0449 in these patients.

To characterize the pharmacokinetic properties of GDC-0449 following a single dose and multiple doses.

To determine the recommended phase II dose and schedule of GDC-0449 for efficacy testing based on achievement of the target exposure with an acceptable safety profile.

Secondary

To determine whether inhibition of Hedgehog (Hh) signaling by GDC-0449 can be reliably measured in human hair follicles and to define the relationship between this pharmacodynamic (PD) effect in surrogate tissue and GDC-0449 dose and exposure.

To make a preliminary assessment of tumor response in patients treated with this drug.

Patients receive oral systemic Hedgehog antagonist GDC-0449 once on day 1 and then once or twice daily beginning on day 8 and continuing for up to 49 weeks in the absence of disease progression or unacceptable toxicity.

No malabsorption syndrome or other condition that would interfere with enteral absorption

No history of significant atherosclerotic disease, including the following:

Coronary artery disease (i.e., myocardial infarction within the past year or unstable angina)

Documented carotid atheromas

No history of congestive heart failure or ventricular arrhythmia requiring medication

No congenital long QT syndrome

No baseline QTc intervals > 0.47 seconds on two of three baseline 12-lead ECGs recorded during the screening period

No active infection requiring intravenous antibiotics

No known HIV infection

No uncontrolled hypocalcemia, hypomagnesemia, or hypokalemia, defined as less than the lower limit of normal for the institution despite adequate electrolyte supplementation

No history of clinically important liver disease, including cirrhosis or viral or other hepatitis

No current alcohol abuse

No significant traumatic injury within the past 3 weeks

No other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the study results or renders the patient at high risk from treatment complications

PRIOR CONCURRENT THERAPY:

At least 4 weeks since prior chemotherapy, investigational therapy, radiotherapy, or major surgical procedure and recovered

No concurrent medications known to prolong the QT interval, including any of the following:

Quinidine or other anti-arrhythmic agents

Haloperidol, fluoxetine, paroxetine, or sertraline

Pentamidine, fluoroquinolone, or macrolide antibiotics

No concurrent medications that may interfere with the metabolism of GDC-0449 (e.g., ketoconazole)

No concurrent grapefruit juice

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Please refer to this study by its ClinicalTrials.gov identifier: NCT00607724